The central theme of Research Project 3 {RP3) is biologic discovery with selective targeted inhibitors of the two signal transduction pathways that are activated most frequently in human cancer: RAS/RAF/ERK and PI3K/AKT/MT0R. Multiple inhibitors of RAF, MEK, P13K, AKT, and mTor are now being developed for the treatment of these tumors. In this proposal. Molecular Imaging (Ml) with PET and MRI w/ill be used as a guide for understanding target inhibition and optimizing these therapeutic regimens. This work is based on recent fundamental studies from our group on pathway regulation and function; effects of inhibitors on components of these pathway; development of Ml modalities for imaging pathway inhibition and tumor response in preclinical models and patients. The recent clinical trial of the RAF inhibitor PLX4032 in melanomas with mutant BRAF was based in large part on our basic findings and resulted in an 85% clinical response rate and serves as proof of principle for the utility of targeting these pathways (NEJM 2010;363:809-19). ERK signaling drives the proliferation of tumors in which it is activated and we have shown that inhibition of the pathway can be imaged effectively with by FLT/PET (Cancer Res. 2007;67:11463-9), In contrast, PI3K/AKT/mTor signaling regulates glucose homeostasis and FDG uptake is very sensitive to mTor inhibitors. These data suggest a role for Ml both as a measure of pharmacodynamic pathway inhibition and tumor response, as well as other changes in tumor biology. For instance, in recent trials, we showed that ERK pathway inhibition induces the iodide transporter and iodine avidity of tumors with mutant BFIAF. The RPS research plan is comprised of the fallowing specific aims. SAl; .Imaging the effects of selective inhibition of P13K signaling in tumors with mutational activation of the pathway. SA2: Imaging the effects of selective inhibition of ERK signaling in tumors with mutant BRAF. SA3: Imaging the effects of combination therapy utilizing inhibitors of P13K or ERK signaling. The major goal of the project is to develop imaging as a tool for measuring the quantitative and temporal effects of targeted drugs on pathway inhibition, tumor biology and tumor growth. The inhibitors we are using are all in or about to enter trials, the major limitations of which are the inability to assess pathway inhibition or to rationally choose combinations, so we expect the findings in this project to be rapidly translated and to have a major clinical impact.